Lipoproteins

Genetic, observational, and interventional studies have unequivocally established that LDL-C and other lipoproteins containing apolipoprotein B (ApoB) are responsible for the development of atherosclerotic cardiovascular disease (ASCVD). The relative risk reduction for cardiovascular disease is proportional to the absolute reduction in LDL-C levels. This relationship holds true regardless of the method or means by which LDL-C is lowered.

Studies involving very low LDL-C levels have shown that the lower the LDL-C level, the lower the cardiovascular risk. To date, very low levels have not shown any negative effects on patients in the available studies.

The basic diagnostics for identifying lipid metabolism disorders include total cholesterol, triglycerides, HDL-C, and LDL-C, which can either be calculated using the Friedewald formula or measured directly. Based on these results, non-HDL-C can be calculated to estimate cardiovascular risk using standardized risk tables. According to the ESC 2021 guidelines, lipid profiling is recommended for all men over the age of 40 and women over 50. In Germany, as part of general preventive check-ups, adults aged 35 and over can have their lipid levels tested every three years. For individuals between 18 and 35, a one-time screening is covered.

Fasting is not required for general screening. However, in patients with metabolic syndrome, type 2 diabetes mellitus, or high triglyceride levels, values calculated using the Friedewald formula should be interpreted with caution.

Corresponding target values for LDL-C, Non-HDL-C, and Apolipoprotein B for patients with low, high, and very high cardiovascular risk.

LDL-C NON-HDL-C Apolipoprotein B

2,6 mmol/l (100 mg/dl) 3,4 mmol/l (100 mg/dl) 100 mg/dl

1,8 mmol/l (70mg/dl) 2,6 mmol/l (70 mg/dl) 80 mg/dl

1,4 mmol/l (55 mg/dl) 2,2 mmol/l (55 mg/dl) 65 mg/dl

Table 4.4.1: Corresponding LDL-C, Non-HDL-C, and Apolipoprotein B target values for patients with low, high, and very high cardiovascular risk
Source: adapted from ESC 2021, page 3275, Table 10

LDL-C

In most studies, LDL-C was calculated using the Friedewald formula:

• LDL cholesterol (mg/dL) = Total cholesterol − HDL cholesterol − Triglycerides / 5
• LDL cholesterol (mmol/L) = Total cholesterol − HDL cholesterol − Triglycerides / 2.2

➞ The formula cannot be used if triglyceride levels are above 400 mg/dL (10.4 mmol/L).

Triglyceride levels depend on whether the patient is fasting. When using the Friedewald formula, blood should be drawn in a fasting state. Nowadays, there are direct methods for measuring LDL-C. However, the results from these direct methods may be unreliable in patients with hypertriglyceridemia.

4.4.3 Non-HDL-C

Non-HDL-C is calculated by subtracting HDL-C from total cholesterol. Non-HDL-C is a significant independent risk factor and is used to assess individual cardiovascular risk. It can also be used when triglyceride levels are above 400 mg/dL.
If patients are not fasting, the measurement of non-HDL-C still provides an accurate result, including in patients with type 2 diabetes mellitus. It includes not only LDL-C but all ApoB-containing lipoproteins, making it a suitable target parameter, especially in patients with high triglycerides and diabetes mellitus.

John Gofman discovered in 1955 that low HDL-C concentrations are associated with an increased risk of coronary heart disease. It was initially believed that high HDL-C levels could compensate for elevated LDL-C levels. However, HDL-C levels above 60 mg/dL (1.55 mmol/L) do not reduce the risk of cardiovascular disease.
Therefore, there is no linear relationship, and the HDL-C/LDL-C ratio is not predictive of cardiovascular risk.

4.4.4 Apolipoproteins

• Apolipoprotein B (ApoB): Measuring ApoB provides a good estimate of atherogenic lipoproteins (VLDL, IDL, and LDL). Several studies have shown that ApoB is equivalent to LDL-C and non-HDL-C in cardiovascular risk assessment.
• Apolipoprotein A1 (ApoA1): ApoA1 is the main protein component of HDL-C. Each HDL-C particle contains between one and five ApoA1 molecules.

4.4.5 Triglycerides (TG)

High triglyceride levels (fasting >150 mg/dL or >1.8 mmol/L) are primarily caused by metabolic syndrome, diabetes mellitus, and other underlying conditions. Rarely, they are due to monogenic hypertriglyceridemias, which can lead to very high triglyceride levels and an increased risk of pancreatitis.

Patients with metabolic syndrome typically have low HDL-C levels and elevated triglycerides.

Lipoprotein (a) (Lp[a])

Lp(a) is another independent risk factor that is causally linked to the pathophysiology of atherosclerosis. Lp(a) is essentially genetically determined.

It is recommended to measure Lp(a) once in a patient’s lifetime to detect this genetically significant factor, as it acts additively to LDL-C cholesterol. Targeted therapies are currently in development and are expected by 2025.

Indications
Measuring Lp(a) is not part of routine screening for the general population. However, in patients with high cardiovascular risk or a family history of atherosclerosis, Lp(a) testing should be performed.

Evaluation
If the Lp(a) concentration is significantly below 30 mg/dL (0.78 nmol/L), repeated testing is usually unnecessary. Contrary to common belief, the concentration of Lp(a) can be influenced by “exogenous” factors. It is increased in kidney diseases (such as nephrotic syndrome and chronic renal insufficiency), and decreased in liver diseases, by steroid hormones (estrogens, progestogens, testosterone), thyroid hormones, and in the acute phase following a myocardial infarction.

Statins do not affect Lp(a), while niacin and PCSK9 inhibitors lower Lp(a) by about one-third. Lipoprotein apheresis significantly reduces Lp(a) levels. Concentrations above 30 mg/dL (0.78 mmol/L) should prompt intensive treatment of traditional modifiable risk factors such as LDL-C, high blood pressure, smoking, and diabetes mellitus.

Lowering Lp(a) with niacin is possible, but its clinical significance is unclear, and the drug is no longer available in Germany. Current studies are investigating antisense oligonucleotides and small interfering RNAs. The oligonucleotide pelacarsen was able to reduce Lp(a) concentrations by over 80%. By degrading the mRNA for apolipoprotein(a) in the liver, Lp(a) production can be reduced. These therapies are effective for several months. In a dose-finding study, Lp(a) was reduced by up to 100%.

A small molecule that inhibits the formation of Lp(a) is also being developed and will be orally available, showing Lp(a)-lowering effects as well.

If clinically indicated (e.g., severe, progressive coronary artery disease despite maximally tolerated lipid-lowering therapy), elimination of Lp(a) via lipoprotein apheresis may be warranted.

Genotyping

Genetic testing is recommended only for the diagnosis of specific genetic lipid metabolism disorders. In patients with familial hypercholesterolemia, testing for mutations in the LDL receptor, ApoB, and PCSK9 genes should be considered.

Apolipoprotein E (ApoE) exists in three isoforms: ApoE2, ApoE3, and ApoE4. In patients with severe combined dyslipidemia, testing for ApoE2 should be considered. The ApoE2/2 phenotype is associated with Type III hyperlipoproteinemia according to the Fredrickson classification, and carries a significantly increased risk for atherosclerosis.